Debromination

ABSTRACT

A process for 9α-debromination of 9α-bromo-11β-hydroxy steroids without eliminating the 11β-hydroxyl group utilizing chromous chloride or chromous sulfate and thioglycolic acid.

DESCRIPTION CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation-in-part of co-pending patentapplication Ser. No. 213,447, filed Dec. 5, 1980.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 3,480,622 discloses a process for debromination of a9α-bromo-11β-hydroxy steroid by reaction with a salt of a polyvalentmetal (Cr) which is in a lower state of valence (+2) capable of beingoxidized to a higher state (+3) in the presence of a substance (thiol)capable of providing hydrogen radicals. The reducing agent waspreferably a chromous salt of an organic carboxylic acid, preferablychromous acetate. Listed as suitable to provide hydrogen radicals were anumber of substances, including thiols which could carry varioussubstituents including carboxyl groups. However, it was preferred thatthe substituent be lower alkyl or unsubstituted aryl groups such asphenyl. A mechanistic explanation for the above is set forth inTetrahedron Letters 43, 3151 (1964) and a more detailed account is foundin J. Am. Chem. Soc. 88, 3016 (1966).

J. Fried and E. F. Sabo in J. Am. Chem. Soc. 79, 1130 (1957) discussedthe problems of trying to debrominate a 9α-bromo-11β-hydroxy steroid toform the corresponding 11β-hydroxy steroid. Using chromous chloride andzinc in acetic acid, they obtained the pure 9(11)-dehydro compound inabout 80% yield, page 1131.

BRIEF DESCRIPTION OF THE INVENTION

Refer to Charts A thru D.

Disclosed is a process for the preparation of an 11β-hydroxy steroidwhich comprises reacting a 9α-bromo- or 9α-chloro-11β-hydroxy steroidwith chromous sulfate or chromous chloride or mixtures thereof andHS--CH₂ --COOH.

Further disclosed is a process for the preparation of an 11β-hydroxypregnane (II), which comprises reacting a 9α-halo-11β-hydroxy pregnane(I) with chromous chloride or chromous sulfate or mixtures thereof andHS--CH₂ --COOH.

Also disclosed is a process for the preparation of an 11β-hydroxyandrostane (IV), which comprises reacting a 9α-halo-11β-hydroxyandrostane (III) with chromous chloride or chromous sulfate or mixturesthereof and HS--CH₂ --COOH.

Disclosed is a process for the preparation of an11β,17α-dihydroxyprogesterone (VI), which comprises reacting a9α-halo-11β,17α-dihydroxyprogesterone (V) with chromous chloride orchromous sulfate, or mixtures thereof, and HS--CH₂ --COOH.

Also disclosed is a process for the preparation of an11β-hydroxyprogesterone (VIII), which comprises reacting a9α-halo-11β-hydroxyprogesterone (VII) with chromous chloride or chromoussulfate, or mixtures thereof, and HS--CH₂ --COOH.

DETAILED DESCRIPTION OF THE INVENTION

A large number of commercially available pharmacologically activesteroids have 11β-hydroxy-Δ⁴ -3-keto or 11β-hydroxy-Δ¹,4 -3-ketofunctionality. These steroids include hydrocortisone,11β-hydroxyprogesterone, prednisolone, 6α-methylprednisolone, and16-methylprednisolone and analogues thereof. In the process ofintroducing the 11β-hydroxyl group, a 9α-halo (chlorine or bromine atom)is also sometimes introduced. Therefore, it would be desirable to have aprocess which would dehalogenate a 9α-chloro or 9α-bromo-11β-hydroxysteroid (I, III, V or VII) to the corresponding 11β-hydroxy steroid (II,IV, VI or VIII). Most known processes produce too much of the9(11)-unsaturated by-product to be of value, see J. Am. Chem. Soc. 79,1130 (1957). A process capable of being developed commercially wasdisclosed in U.S. Pat. No. 3,480,622.

The process of U.S. Pat. No. 3,480,622 involved reacting a9α-bromo-11β-hydroxy steroid (I, III, V, or VII) with a salt of apolyvalent metal in which the metal is capable of being oxidized to ahigher valence state in the presence of a substance capable of providinghydrogen free radicals.

In U.S. Pat. No. 3,480,622, the metal ion reducing agents includedferrous, titanous, thallous, stannous and chromous salts. Chromous saltswere preferred used as the salt of an organic carboxylic acid,preferably a lower (C₁₋₆) alkanoic acid such as acetic, propionic orbutyric. Chromous acetate was "especially suitable."

It has been discovered that chromous chloride or chromous sulfate ormixtures thereof are preferable reducing agents. Chromous chloride orchromous sulfate have the advantage of greater ease of preparation,storage and handling. These reagents can also be prepared in higheryield than chromous acetate. A slight excess of chromous sulfate overtheory brings about rapid (5 to 15 minutes) and complete reduction of9α-bromo-11β-hydroxysteroids when used with the co-reductantthioglycolic acid.

In U.S. Pat. No. 3,480,622, the substances capable of providing hydrogenradicals included H₃ PO₂, hydrides such as triarylsilanes or triaryltinhydrides, 1,4-dihydroaromatic compounds such as 1,4-dihydrobenzene and1-benzyl-1,4-dihydronicotinamide and related dienes such ascyclopentadiene and in particular thiols. The thiols were alleged tohave greatly increased the yield of the desired dehalogenated product.The thiols could be aliphatic, araliphatic or aromatic and can ". . .carry any substituents such as hydroxy, ether, thioether, keto,carboxyl, esterified carboxyl groups, etc." If further stated that theunsubstituted hydrocarbon groups are preferred. Therefore, while U.S.Pat. No. 3,480,622 disclosed the use of thiols substituted with carboxylgroups, the patent actually taught away from this group by preferring"Unsubstituted hydrocarbon groups," specifying ". . . lower alkyl groupsor unsubstituted aryl groups such as phenyl."

It has been discovered that thioglycolic acid surprisingly andunexpectedly increases the yield over that which is expected and greatlysimplifies the work-up procedure. The use of thioglycolic acid permits(1) a more versatile choice of reactant medium, (2) faster reactions,(3) greater ease of product isolation and (4) higher yields of11β-hydroxy steroid product (II or IV).

Virtually all 9α-chloro- or 9α-bromo-11β-hydroxy steroids can be used inthe present process. The preferred 9α-halo-11β-hydroxy startingmaterials (I, III, V, or VII) are well known to those skilled in the artor can be readily prepared by means well known to those skilled in theart from known starting materials. It is preferred that R₉ is bromine.

Polar inert solvents such as DMF, THF, and methanol give high yields.

Temperature is not critical, -50° to 100°0 being suitable, 20°-50° beingpreferred.

Upon completion of the reaction as monitored by TLC, the reactionmixture is diluted with a volume of water greater than the total volumeof the reaction mixture, preferably 2-10 times the reaction mixturevolume. After addition of the water, the reaction mixture is stirred andthen filtered. The filter cake is washed and then processed in anappropriate manner, depending on the next chemical reaction it willundergo. The filtrate can be extracted with an organic solvent to obtainadditional product.

DEFINITIONS

The definitions and explanations below are for the terms as usedthroughout the entire patent application, including both thespecification and claims.

All temperatures are in degrees Centigrade.

TLC refers to thin-layer chromatography.

GLC refers to gas-liquid chromatography.

THF refers to tetrahydrofuran.

DMF refers to dimethylformamide.

DMSO refers to dimethylsulfoxide.

Saline refers to an aqueous saturated sodium chloride solution.

R₆ is a fluorine atom or methyl group.

R₉ is a chlorine or bromine atom.

R₁₆ is a hydrogen atom or α- or β-methyl or α-hydroxyl group, when R₁₆is α-hydroxyl and when R₁₇ is a hydrogen atom, R₁₆ and R₁₇ can be a16,17-acetonide.

R₁₇ is a hydrogen atom or a group of the formula --COR_(17A) whereR_(17A) is alkyl of 1 thru 4 carbon atoms or phenyl, when R₁₇ is ahydrogen atom and when R₁₆ is α-hydroxyl, R₁₆ and R₁₇ can be a16,17-acetonide.

R₂₁ is a hydrogen atom or a group of the formula --COR_(21A) whereR_(21A) is alkyl of 1 thru 4 carbon atoms or phenyl.

˜ indicates the attached group can be in either the α or βconfiguration.

is a single or double bond.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely ilustrative, and not limiting ofthe preceding disclosure in any way whatsoever.

Example 1 Hydrocortisone acetate (II)

A mixture of 9α-bromohydrocortisone acetate (I, 6.90 g) and thioglycolicacid (5.5 ml) in DMF (31 ml) is warmed to 45° with stirring undernitrogen. Over a period of about 5 minutes, a chromous sulfate solution(1.4 M, 13 ml) is added. The resulting mixture is stirred for 10 minutesand then cooled in an ice-water bath. The mixture is diluted with water(200 ml) and stirred at 5° for 30 minutes. The mixture is then filteredand the filter cake washed several times with water. The product is airdried to give the title compound, one spot by TLC, (5.15 g 89.2%chemical yield), which is identical with an authentic sample. Anadditional 3% of the title compound is obtained by liquid-liquidextraction of the filtrate.

Example 26α-Fluoro-11β,16α,17α,21-tetrahydroxypregn-4-ene-3,20-dione-16,17-acetonide21-acetate (II)

9α-Bromo-6α-fluoro-11β,16α,17α,21-tetrahydroxypregn-4-ene-3,20-dione-16,17-acetonide21-acetate (I, 10.8 g) and thioglycolic acid (8.06 ml) are dissolved inDMSO (200 ml) and the mixture under nitrogen is cooled to 15°. Chromoussulfate (0.91 N aqueous solution, 21 ml) is added over a 36-minuteperiod at 15°-16° followed by the addition of water (700 ml, pre-cooledto 1°) over a 2-minute period. The mixture is stirred for 10 minutes andthe slurry is then filtered. The solids are washed with water to givethe title compound.

Example 3 Prednisolone (II)

Following the general procedure of Example 1 and making non-criticalvariations but starting with either 9α-chloro or 9α-bromoprednisolone(I), the title compound is obtained.

Example 4 6α-Methylprednisolone (II)

Following the general procedure of Example 1 and making non-criticalvariations but starting with either 9α-chloro or9α-bromo-6α-methylprednisolone (I), the title compound is obtained.

Example 5 11β-Hydroxyandrost-4-ene-3,17-dione (IV)

A solution of 9α-bromo-11β-hydroxyandrost-4-ene-3,17-dione (III, 3.00 g)thioglycolic acid (3.0 ml) in DMF (17 ml) is stirred under nitrogen in a45°-50° water bath. A chromous sulfate solution (1.4 M, 7.0 ml) is addeddropwise over about 5 minutes. The mixture is allowed to cool, and theresulting slurry is diluted by slow addition of water (50 ml). Themixture is cooled to about 5° and filtered. The filter cake is washedwith water and air dried to give the title compound (2.03 g, 85.3%chemical yield) which is identical with an authentic sample. Thefiltrate is extracted to give additional material (0.34 g, 14.3%).

Example 6 11β-Hydroxyandrost-4-ene-3,17-dione (IV)

A solution of 9α-bromo-11β-hydroxyandrost-4-ene-3,17-dione (III, 2.00g), thioglycolic acid (2.0 ml) in THF (20 ml) and water (5 ml) isstirred under nitrogen at 20°-25°. A chromous sulfate solution (1.4 M,5.5 ml) is added and the two-phase system is stirred. After four hours,another 4.5 ml of chromous sulfate solution is added and the mixturestirred overnight. The mixture is diluted with water and extracted withethyl acetate. The ethyl acetate extracts are washed with water, adiluted sodium hydroxide solution, water and saline. The organic phaseis dried over sodium sulfate and concentratd to a solid. The solid iscrystallized from benzene-hexane to give a first crop of crystals of thetitle compound (1.38 g, 83.5% chemical yield) which are measured to be99% pure as measured by GLC and is identical to an authentic sample.

Example 7 11β-Hydroxyandrost-4-ene-3,17-dione (IV)

A mixture of 9α-bromo-11β-hydroxyandrost-4-ene-3,17-dione (III, 0.25 g),zinc dust (0.15 g), chromic sulfate hydrate (0.05 g), thioglycolic acid(1 ml) and DMF (20 ml) are stirred under nitrogen at 20°-25° for 20hours. The crude product is isolated as in Example 3 and is shown by GLCto be the title compound in 83% chemical yield.

Example 8 6α-Fluoro-11β-hydroxy-16α-methylpregna-1,4-diene-3,20-dione(VIII)

Following the general procedure of Example 1 and making non-criticalvariations but starting with9α-bromo-6α-fluoro-16α-methylpregna-1,4-diene-3,20-dione (VII) the titlecompound is obtained. ##STR1##

I claim:
 1. A process for the preparation of an11β,17α-dihydroxyprogesterone of the formulawhich comprises reacting a9α-halo-11β,17α-dihydroxyprogesterone of the formula ##STR2## withchromous sulfate or chromous chloride or mixtures thereof and HS--CH₂--COOH, where R₆, R₉, R₁₆, R₁₇, and ˜ are defined in the specification.2. A process for preparing an 11β-hydroxyprogesterone of the formula##STR3## which comprises reacting a 9α-halo-11β-hydroxyprogesterone ofthe formula ##STR4## with chromous sulfate or chromous chloride ormixtures thereof and HS--CH₂ --COOH, where R₆, R₉, R₁₆, R₁₇, and ˜ aredefined in the specification.
 3. A process according to claim 1 or 2which uses chromous sulfate.
 4. A process according to claim 1 or 2which uses chromous chloride.
 5. A process according to claim 1 or 2which uses a mixture of chromous sulfate and chromous chloride.
 6. Aprocess according to claim 1 or 2 where R₉ is a bromine atom.
 7. Aprocess according to claim 1 or 2 where R₉ is a chlorine atom.
 8. Aprocess according to claim 2 where where the 11β-hydroxyprogesterone(VIII) is 6α-fluoro-11β-hydroxy-16α-methylpregna-1,4-diene-3,20-dione.